CN114469912A - Use of endoxinolate in preparation of medicine for treating diseases caused by novel coronavirus - Google Patents

Use of endoxinolate in preparation of medicine for treating diseases caused by novel coronavirus Download PDF

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CN114469912A
CN114469912A CN202111626304.5A CN202111626304A CN114469912A CN 114469912 A CN114469912 A CN 114469912A CN 202111626304 A CN202111626304 A CN 202111626304A CN 114469912 A CN114469912 A CN 114469912A
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hydrochloride
novel coronavirus
coronavirus sars
sars
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邬开朗
刘芳
郭铭
王欣
向文杰
张艳
朱莹
黄智强
祝成亮
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Zhongshan Yiweidi Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

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Abstract

The invention discloses application of inner oxiphenate in preparing medicine for preventing and/or treating diseases caused by novel coronavirus. Inecoxiphenate is a small molecule compound, the CC of which50It was 124.7. mu.M. The invention discovers for the first time that the inner oximate hydrochloride can inhibit the replication of the novel coronavirus SARS-CoV-2 in a dose-dependent manner, and the IC thereof50(median inhibitory concentration): intracellular at 0.91. mu.M, extracellular at 0.77. mu.M, and Selection Indices (SI) of approximately 137 (intracellular) and 162 (extracellular), indicating that the endoxinolate is a low-toxicity and highly potent agent against the novel coronavirus SARS-CoV-2.

Description

Use of endoxinolate in preparation of medicine for treating diseases caused by novel coronavirus
Technical Field
The invention relates to the technical field of medicines, in particular to application of Endoxifen hydrochloride (CAS:1032008-74-4) in preparation of a medicine for preventing and/or treating diseases caused by novel coronaviruses.
Background
The novel coronavirus (SARS-CoV-2) is the causative agent of the novel coronavirus pneumonia (COVID-19). Both SARS-CoV-2 and SARS-CoV viruses belong to the family of Coronaviridae (Coronavir), the genus of coronavirus beta. SARS-CoV-2 is a positive-stranded single-stranded RNA coronavirus. The RNA sequence was about 30kb in length. The outer Membrane of the COVID-19 virion is composed of 4 structural proteins, including N protein (Nucleocapsid protein), S protein (Spikeprotein), E protein (Envelope protein) and M protein (Membrane protein). The S protein therein determines the host range and specificity of the virus. To date, no specific medicine is available for curing the novel coronavirus pneumonia. Therefore, the development of corresponding anti-new coronavirus drugs is also crucial to completely overcome new coronavirus.
Endoxinolate, english name: endoxifen hydrochloride, CAS:1032008-74-4, the structural formula is shown as the following formula (I),
Figure BDA0003439768280000011
the inner oxifene hydrochloride is an active metabolite of Tamoxifen and is a potent selective estrogen receptor antagonist. Has breast tumor resisting activity. However, no reports on the resistance of the novel coronavirus are found.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the application of the inner oxigenin hydrochloride in preparing the medicine for preventing and/or treating the diseases caused by the novel coronavirus SARS-CoV-2.
Specifically, in order to solve the technical problem of the present invention, the following technical scheme is adopted:
in a first aspect, the present invention provides the use of a lactone hydrochloride salt of a compound of formula (I) in any one of X1) -X5) as follows:
Figure BDA0003439768280000021
x1) preparing products for preventing and/or treating diseases caused by novel coronavirus SARS-CoV-2;
x2) preparing products for preventing and/or treating the infection of the novel coronavirus SARS-CoV-2;
x3) preparing novel coronavirus SARS-CoV-2 inhibitor;
x4) preparing a product for inhibiting the proliferation of the novel coronavirus SARS-CoV-2;
x5) to prepare the product for inhibiting the cytopathic effect of the novel coronavirus SARS-CoV-2.
Preferably, in the above applications, the compound of formula (I) may be used as the sole active ingredient, or may be used as the active ingredient together with one, two or more other antiviral drugs.
Preferably, the other antiviral drug is selected from ganciclovir, acyclovir, amantadine, rimantadine, oseltavir, abacavir, acemenan, acyclovir sodium, adefovir, alovudine, avsunotol, amantadine hydrochloride, aradinodine, oreridone, atidine mesylate, avridine, cidofovir, cidofophylline, emtricitabine, cytarabine hydrochloride, delavirdine mesylate, desciclovir, didanosine, dioxazoline, edexuridine, esmivir, eltamitriptyline, emlaraden, emviroxime, hoplatin, famciclovir, cloquine hydrochloride, fexitabine, fexuridine, fosamivir, foscarnet, fosamivir sodium, ganciclovir sodium, idoside, indinavir, ethoxybutovidone aldehyde, lamivudine, lubucavir, loperavir hydrochloride, lopinavir hydrochloride, mepiridine, mevidine hydrochloride, domethamine, foscamostatin, foscamycin sodium, foscamitabine, valacyclovir hydrochloride, valacil, valaciclovir hydrochloride, valacitretin, valaciclovir hydrochloride, valcanine hydrochloride, valaciclovir hydrochloride, valacitretin, valcanine hydrochloride, valcanine hydrochloride, valaciclovir hydrochloride, valacil, valacitretin, valcanine hydrochloride, valacitretin, valcanine hydrochloride, valcanine, and other, The composition comprises the components of methylthioninium chloride, nelfinavir, nelavir, penciclovir, pirodavir, ribavirin, saquinavir mesylate, ritonavir, sotalomide hydrochloride, solivudine, penicillin, stavudine, tenofovir, teluovir hydrochloride, trovudine, valacyclovir hydrochloride, vidarabine phosphate, vidarabine sodium phosphate, tipranavir, viruoxime, zalcitabine, zidovudine and neat viroxime.
Preferably, in the above application, the disease caused by the novel coronavirus SARS-CoV-2 is infectious disease caused by SARS-CoV-2 or its complication; further preferably, the infectious disease is a respiratory tract infectious disease.
Preferably, the product is a medicament.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for use in any one of X1) -X5) as follows:
x1) preparing products for preventing and/or treating diseases caused by novel coronavirus SARS-CoV-2;
x2) preparing products for preventing and/or treating SARS-CoV-2 infection;
x3) preparing novel coronavirus SARS-CoV-2 inhibitor;
x4) preparing a product for inhibiting the proliferation of the novel coronavirus SARS-CoV-2;
x5) to prepare the product for inhibiting the cytopathic effect of the novel coronavirus SARS-CoV-2.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Preferably, the carrier includes, but is not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.). Among these, water-soluble carrier materials are preferred.
Preferably, conventional cosolvents, buffers, pH adjusters, and the like may also be added to the pharmaceutical composition.
Preferably, colorants, preservatives, flavors, flavorants, sweeteners, or other materials are added to the pharmaceutical composition.
Preferably, the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder injections and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field. The preparation can be used for injection administration, including subcutaneous injection, intravenous injection, intramuscular injection, intracavity injection and the like; luminal, e.g., rectal and vaginal; administration to the respiratory tract, e.g., nasally; administration to the mucosa.
The invention has the beneficial effects that:
the invention discovers for the first time that the compound (inner oxigenin hydrochloride) in the formula (I) can inhibit the proliferation of the novel coronavirus SARS-CoV-2 and infect host cells, and can be used for treating diseases caused by the novel coronavirus infection.
The compound of formula (I) is a small molecule compound, CC thereof50At 124.7. mu.M, it was able to dose-dependently inhibit the replication of the novel coronavirus SARS-CoV-2, its IC50(median inhibitory concentration) was 0.91. mu.M. The Selection Index (SI) is about 137. The compound of formula (I) is described as a low-toxicity and high-efficiency medicament against the novel coronavirus SARS-CoV-2.
Drawings
FIG. 1 is a schematic representation of the cytotoxicity assay of a compound of formula (I).
FIG. 2 is a graph of the efficiency of viral replication in treating cells infected with the novel coronavirus SARS-CoV-2 with a compound of formula (I).
FIG. 3 is a graph showing the virus replication efficiency of a compound of formula (I) in the supernatant of culture medium of cells infected with SARS-CoV-2, a novel coronavirus.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations.
Definition and description:
as used herein, the terms "comprising," "having," "including," or "containing" are intended to be inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
The definition of "or" as used herein is merely alternatives and "and/or," but the term "or" in the claims means "and/or" unless explicitly indicated to be only alternatives or mutual exclusions between alternatives.
Unless defined otherwise or clearly indicated by the background, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
At present, the cell culture model for in vitro screening of anti-novel coronavirus SARS-CoV-2 medicine is the most commonly used screening model, and has the advantages that: can provide a large number of cells with the same genetic characters as research objects, is convenient to operate, can eliminate the influence of other external factors, can detect the effective concentration and the therapeutic index of the medicament, and provides more bases for later mechanism research. The invention adopts a cell culture screening method to detect the influence of the compound shown in the formula (I) on Caco-2 cells infected by the novel coronavirus SARS-CoV-2, and quantitatively analyzes the activity of the compound shown in the formula (I) for resisting the novel coronavirus SARS-CoV-2 based on the detection of the copy number of the virus nucleic acid in a supernatant and cells.
Example 1: evaluation of the Activity of the Compound of formula (I) (Ennoxidate) against novel coronaviruses
1. Experimental Material
1.1 cells, viruses and drugs
Caco-2 cells were purchased from ATCC (cat # HTB-037).
SARS-CoV-2 live virus (accession number IVCAS 6.7512).
Compounds of formula (I) (CAS:1032008-74-4) were purchased from Sigma.
1.2 reagents
DMEM medium and FBS were purchased from GIBCO; CCK8 cell activity assay kit was purchased from Thermofisher; SYBR Mixed solution (iTaq)TMUniversal
Figure BDA0003439768280000051
Green Supermix) was purchased from Bio-Rad Inc.
1.3 Experimental instruments
Quantitative PCR instrument (Bio-Rad CFX96 Touch)TMReal-Time PCR detection system) was purchased from Bio-Rad. Multi-labeled microplate readers were purchased from PerkinElmer corporation.
Figure BDA0003439768280000052
1.0R type refrigerated centrifuge and cell culture chamber were purchased from Thermofeisher company.
2. Experimental methods and results
2.1 cell culture
37℃，5％CO2Culturing in a humidifying incubator. DMEM medium containing 10% FBS, 100U/mL penicillin and streptavidin was used. Cells were passaged to 90% confluence at a passage ratio of 1/3-1/4.
2.2 Virus culture
200 mul/tube and frozen at-70 ℃ for later use.
2.3 cytotoxicity assays for Compounds of formula (I)
Caco-2 cells were 8X 103Cells/well (100 μ l) are inoculated in a 96-well cell culture plate, and the cells are kept for later use after adherence; the drug was treated with cell maintenance medium (DMEM + 2% serum) at 200.0. mu.M maximum concentration in a total of 6 gradients (200. mu.M, 100. mu.M, 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M) diluted in 2-fold gradients, 3 replicates per gradient. And (3) discarding the culture supernatant after 48h of culture, adding 10 mu l of reagent containing CCK8 into each well, placing the mixture into a cell culture box for continuous culture for 1h, measuring the absorbance at 450 mu M by using a microplate reader after 1h, and calculating the survival rate of the cells.
The results show (FIG. 1) CC of Caco-2 cells by the compound of formula (I)50It was 124.7. mu. mol/l. In the range of less than 100 mu MThe compound has no cytotoxicity to Caco-2 cells, and the application range of the compound shown in the formula (I) is relatively safe, namely the administration dosage of the compound shown in the formula (I) is 0.25-4.0 mu M according to cell experiments.
2.4 detection of the efficiency of the Compounds of formula (I) in inhibiting the replication of SARS-CoV-2 based on fluorescent quantitative PCR
2.4.1. The following experiments were all performed in the BSL-3 laboratory:
caco-2 cells were plated at 1.0X 104Inoculating the cells/hole into a 48-hole cell culture plate, culturing for 14-18 h in a 37 ℃ cell culture box, and standing until the cells grow into a monolayer. The medium in the well plate was discarded, washed twice with PBS, and then a total of 500. mu.l of 0.5MOI virus solution and each concentration gradient drug was added and cultured in a cell incubator at 37 ℃. The drug was initially concentrated at 4.0 μ M and serially diluted in 5 gradients of 2-fold gradient, with 3 duplicate wells per gradient. After 48h of culture, taking supernatant and cells of each experimental hole to extract RNA, carrying out reverse transcription to obtain cDNA, and then carrying out fluorescent quantitative PCR detection. The experiment was set up with a blank control group, a positive control group (Reidesvir), a negative control group (no drug treatment after viral infection) and an experimental drug group.
2.4.2.48 h later, collecting cell supernatant and cells by Trizol LS respectively, and carrying out virus inactivation to a biological safety level three (BSL-3) laboratory. Used for RNA extraction.
2.4.3. RNA was extracted from supernatant and cells as described in the Tianmo Tech Inc TR205-50 kit.
2.4.4. The RNA obtained was reverse transcribed into cDNA according to the instructions of the Hill ZR102 reverse transcription kit.
2.4.5. The level of genome replication was detected by the quantitative genome PCR method (QPCR). The quantitative PCR primers are directed at the S2 gene sequence of SARS-CoV-2, and the quantitative PCR primers are as follows:
5'-GCTGGTGCTGCAGCTTATTA-3'；
5'-AGGGTCAAGTGCACAGTCTA-3'。
housekeeping gene GADPH was selected as the corrected internal reference control gene and quantitative PCR primers for GADPH were as follows:
5'-GCTCCCTCTTTCTTTGCAGCAAT-3'；
5'-TACCATGAGTCCTTCCACGATAC-3'。
2.4.6. the quantitative Ct values were corrected by the reference Gene (GAPDH) and the inhibition was calculated by the formula: the rate of inhibition of viral replication was (1-drug group/negative control group) × 100%. Results mean, standard deviation and IC were calculated by GraphPad Prism 8 software50。
2.4.7. The results of the calculation in step (2.4.6) were used to plot the inhibition of SARS-CoV-2 replication by compound of formula (I). The results are shown in FIGS. 2 and 3.
Figure 2 results show that: in Caco-2 cells, the compounds of formula (I) are capable of dose-dependently inhibiting the level of SARS-CoV-2 replication, its IC for SARS-CoV-2 replication50(median inhibitory concentration) was 0.91. mu. mol/l.
Figure 3 the results show: the compounds of formula (I) are capable of dose-dependently inhibiting the level of SARS-CoV-2 replication in the supernatant of Caco-2 cell culture, its IC for SARS-CoV-2 replication50(half maximal inhibitory concentration) was 0.77. mu. mol/l.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Sequence listing
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Claims (10)

1. Use of a compound of formula (I) as an internal salt of a phenolate in any one of the following X1) -X5):
Figure FDA0003439768270000011
x1) preparing products for preventing and/or treating diseases caused by novel coronavirus SARS-CoV-2;
x2) preparing products for preventing and/or treating the infection of the novel coronavirus SARS-CoV-2;
x3) preparing novel coronavirus SARS-CoV-2 inhibitor;
x4) preparing a product for inhibiting the proliferation of the novel coronavirus SARS-CoV-2;
x5) to prepare the product for inhibiting the cytopathic effect of the novel coronavirus SARS-CoV-2.
2. The use according to claim 1, wherein the disease caused by the novel coronavirus SARS-CoV-2 is an infectious disease caused by SARS-CoV-2 or a complication thereof; further preferably, the infectious disease is a respiratory infectious disease.
3. Use according to claim 2, characterized in that the compound of formula (I) is used as the sole active ingredient; or as an active ingredient together with one, two or more other antiviral drugs;
preferably, the other antiviral drug is selected from ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemenan, acyclovir sodium, adefovir, alovudine, avsunotol, amantadine hydrochloride, aradinodine, oreridone, atidine mesylate, avridine, cidofovir, cidofophylline, emtricitabine, cytarabine hydrochloride, delavirdine mesylate, desciclovir, didanosine, dioxazoline, edexuridine, emivirin, eltamicitabine, emlarden, engixime, hoplatin, famciclovir, cloquine hydrochloride, decitabine, fexitabine, fexiuridine, fosfomid, foscarnet, ganciclovir sodium, idoside, indinavir, ethoxybutaneone aldehyde, lamivudine, lubucacavir, lopanavir hydrochloride, lopinavir hydrochloride, dometacin, domethamine, domastine hydrochloride, foscamostatin, valcamtin, valacyclovir, valcamine, valcamitabine, valdecoxib, valacyclovir hydrochloride, valcanine, valacil, valcanine hydrochloride, valacitretin, valdecoxib, valcanine hydrochloride, valacitretin, valacil, valacitretin, valcanine, valprovir hydrochloride, and other, The composition comprises the components of methylthioninium chloride, nelfinavir, nevirapine, penciclovir, pirodavir, ribavirin, saquinavir mesylate, ritonavir, sotalomide hydrochloride, solivudine, penicillin, stavudine, tenofovir, troglonol hydrochloride, trifluridine hydrochloride, valacyclovir hydrochloride, vidarabine phosphate, vidarabine sodium phosphate, tipranavir, viruoxime, zalcitabine, zidovudine and neat viroxime.
4. Use according to any one of claims 1 to 3, wherein the product is a medicament.
5. Use of a pharmaceutical composition comprising a compound of formula (I) in any one of the following X1) -X5):
Figure FDA0003439768270000021
x1) preparing products for preventing and/or treating diseases caused by the novel coronavirus SARS-CoV-2;
x2) preparing products for preventing and/or treating the infection of the novel coronavirus SARS-CoV-2;
x3) preparing novel coronavirus SARS-CoV-2 inhibitor;
x4) preparing a product for inhibiting the proliferation of the novel coronavirus SARS-CoV-2;
x5) to prepare the product for inhibiting the cytopathic effect of the novel coronavirus SARS-CoV-2.
6. The use of claim 5, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier;
preferably, the carrier includes, but is not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.); further preferred are water-soluble carrier materials.
7. The use according to claim 5, wherein conventional cosolvents, buffers, pH regulators and the like may also be added to the pharmaceutical composition.
8. Use according to claim 6, characterized in that colorants, preservatives, flavors, sweeteners or other materials are added to the pharmaceutical composition.
9. The use according to any one of claims 5 to 8, wherein the pharmaceutical composition is in the form of a formulation including, but not limited to, tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder injections.
10. The use of claim 9, wherein the dosage form of claim 9 is administered by injection, including subcutaneous, intravenous, intramuscular, and intracavity; for luminal administration, such as rectally and vaginally; administration to the respiratory tract, e.g., nasally; administration to the mucosa.
CN202111626304.5A 2021-12-28 2021-12-28 Use of endoxinolate in preparation of medicine for treating diseases caused by novel coronavirus Pending CN114469912A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257940A1 (en) * 2020-06-18 2021-12-23 The Cleveland Clinic Foundation Treatment of viral infections with estrogen receptor modulators and anti-inflammatory agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257940A1 (en) * 2020-06-18 2021-12-23 The Cleveland Clinic Foundation Treatment of viral infections with estrogen receptor modulators and anti-inflammatory agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHULONG ZU 等: "Tamoxifen and clomiphene inhibit SARS-CoV-2 infection by suppressing viral entry", SIGNAL TRANSDUCTION AND TARGETED THERAP *

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